Obesity is the cause of much morbidity and mortality in the US. Great strides have been made recently in determining the endocrine mechanisms and neuroanatomical pathways that are involved in the development of obesity. One such mechanism involves ghrelin, a hormone that stimulates food intake in animals and whose levels are raised in association with hunger, diet-induced weight loss and certain forms of obesity in humans. The primary purpose of this proposal is to gain a better understanding of ghrelin's role in the regulation of feeding behavior and body weight. The proposed experiments include transgenic and neuroanatomical approaches to determine the central expression patterns of ghrelin's receptor (GHSR), to determine the chemical phenotypes of these ghrelin-responsive neurons and to determine whether these ghrelin-responsive neurons innervate key autonomic, neuroendocrine and behavioral control sites in the brain. Other proposed experiments include disruption of ghrelin's signaling capacity, by deletion of its receptor, to determine if an intact, ghrelin-engaged neuronal circuitry is required for normal body weight homeostasis and the coordinated responses to fasting. Finally, the proposal aims to resolve a debate in the scientific community regarding whether ghrelin is expressed in the brain. We hope that this study will better enable the design of therapeutics to treat and prevent obesity and its co-morbid conditions.